Study Links Cases of ALS and FTD to a Huntington’s Disease-Associated Mutation

Summary: Researchers find a previously unknown connection between ALS, FTD, and the Huntington’s disease-associated gene, huntingtin.

Source: NIH

A study led by researchers at the National Institutes of Health has made a surprising connection between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two disorders of the nervous system, and the genetic mutation normally understood to cause Huntington’s disease.

This large, international project, which included a collaboration between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), opens a potentially new avenue for diagnosing and treating some individuals with FTD or ALS.

Several neurological disorders have been linked to “repeat expansions,” a type of mutation that results in abnormal repetition of certain DNA building blocks. For example, Huntington’s disease occurs when a sequence of three DNA building blocks that make up the gene for a protein called huntingtin repeats many more times than normal. These repeats can be used to predict whether someone will develop the illness and even when their symptoms are likely to appear, because the more repeats in the gene, the earlier the onset of disease.

“It has been recognized for some time that repeat expansion mutations can give rise to neurological disorders,” said Sonja Scholz, M.D., Ph.D., investigator, NINDS Intramural Research Program. “But screening for these mutations throughout the entire genome has traditionally been cost-prohibitive and technically challenging.”

Taking advantage of technology available at NIH, the researchers screened the entire genomes from large cohorts of FTD/ALS patients and compared them to those of age-matched healthy individuals. While several patients had a well-established genetic marker for FTD/ALS, a small subset surprisingly had the same huntingtin mutation normally associated with Huntington’s disease. Remarkably, these individuals did not show the classical symptoms of Huntington’s but rather those of ALS or FTD.

“None of these patients’ symptoms would have clued their physicians into thinking that the underlying genetic cause was related to the repeat expansion we see in Huntington’s disease,” said Dr. Scholz.

She continued by explaining that whole genome sequencing is changing how neurological patients can be diagnosed. Traditionally, this has been based on which disease best fit the overall symptoms with treatment aimed at managing those symptoms as best as possible. Now, clinicians can generate genetically defined diagnoses for individual patients, and these do not always align with established symptom-based neurological conditions.

“Our patients simply don’t match a textbook definition of disease when it comes to which mutation produces which symptoms. Here we have patients carrying a pathogenic huntingtin mutation but who present with FTD or ALS symptoms,” said Dr. Scholz.

This shows DNA
. While several patients had a well-established genetic marker for FTD/ALS, a small subset surprisingly had the same huntingtin mutation normally associated with Huntington’s disease. Image is in the public domain

One implication of these findings is that, if successful, these therapies could be applied to the small subset of FTD and ALS patients with that mutation as well. The researchers note that, while the number of FTD/ALS patients seen with the Huntington’s-linked mutation is small (roughly 0.12-0.14%), adding genetic screening for the mutation to the standard diagnostic procedure for patients showing symptoms of FTD or ALS should be considered.

“Because gene therapy targeting this mutation is already in advanced clinical trials, our work offers real hope to the small number of FTD and ALS patients who carry this mutation,” said Bryan Traynor, M.D., Ph.D., senior investigator, NIA Intramural Research Program. “This type of large-scale international effort showcases the power of genomics in identifying the molecular causes of neurodegenerative diseases and paves the way for personalized medicine.”

Funding: This research was supported by the Intramural Research Program of the National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke; project numbers 1ZIAAG000935, 1ZIANS003154, 1ZIANS003033, 1ZIANS003034), the Intramural Research Program of the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute (IAA-A-HL-007.001), the ALS Association, and The Tow Foundation.

About this genetics research news

Source: NIH
Contact: Carl P. Wonders – NIH
Image: The image is in the public domain

Original Research: Closed access.
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis” by Dewan R. et al. Neuron


Abstract

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Highlights

  • Pathogenic expansions in the HTT gene are a rare cause of FTD/ALS spectrum diseases
  • Autopsies showed both the expected TDP-43 pathology of FTD/ALS and polyQ inclusions
  • HTT repeat expansions were not seen in healthy subjects or Lewy body dementia cases
  • Clinicians should screen FTD/ALS patients for HTT repeat expansions

Summary

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40–64 CAG repeats) in the huntingtin ( HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington’s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Join our Newsletter
I agree to have my personal information transferred to AWeber for Neuroscience Newsletter ( more information )
Sign up to receive our recent neuroscience headlines and summaries sent to your email once a day, totally free.
We hate spam and only use your email to contact you about newsletters. You can cancel your subscription any time.